Two studies provide the data for this project. The CARDIA Study is a prospective, epidemiologic investigation of the determinants and evolution of cardiovascular risk factors among 5,115 African American and white young adults 18-30 years of age at baseline in 1985-86. Participants were recruited from the populations of four geographic locations (Birmingham, AL; Chicago, IL; Minneapolis, MN; and Oakland, CA). The CARDIA Coordinating Center is also located at the University of Alabama-Birmingham. The study population was approximately balanced according to sex (54% women), ethnicity (52% African American), and education (40% with less than equal to 12 years of education) at each center. After the 1984 baseline, there are 9 additional examinations over a 30-year period. In 2010 the CARDIA Brain MRI study was added to the 25-year follow-up exam, and in 2015 year 30 follow-up, the MRI was repeated in the same people. Cognitive data were also collected at the same exam cycle as the MRI. The MRI sub-study aims to identify early and novel brain markers in relation to cardiovascular disease and risk factors. This information could prove critical in prevention and early management of CVD before irreversible damage and functional consequences occurs. It will also provide data on early MRI markers that may predict later age cognitive disorders. AGES- RS is a population-based follow up study of men and women born 1907-1934. The cohort was established in 1967 by the Icelandic Heart Association; participants were followed up to six times. To advance our understanding of genetic and non-genetic risk factors, AGES-RS focuses on obtaining high quality quantitative measures of intermediate components of major diseases of old age. To this end, extensive bio-image and bio-specimen phenotype measures have been made of multiple physiological systems, including neurocognitive, vascular, musculoskeletal, and body composition, and metabolic measures. Participants underwent three extensive exams of cognition and brain MRI. A similar protocol was also used to evaluate 400 offspring of AD cases identified in the AGES-RS. Together these studies have unique and rich data on brain function and structure, including measures of cognition, structural and physiologic measures of the brain, and depression at two different stages in the life course. We are currently conducting Genome Wide Association studies (GWAS) of endophenotypes including cognition, and regional brain tissue volumes, as well as investigating the predictive power of genetic risk scores for clinical and sub-clinical brain disease. Because genetic studies require very large samples, the CARDIA and AGES-RS investigators have pooled brain structure and function data within several international consortia including CHARGE, IGAP, and MetaStroke. To date, genome wide analysis studies have identified three significant pathways that contribute to AD pathogenesis - endolysosomal regulation, lipid metabolism, and immune response pathways. Genetic variants have been identified for several MRI and cognitive phenotypes related to AD, but for the most part, these studies are likely underpowered to identify significant leads for further experimental validation.